US20070197485A1 - Therapy and Use of Compounds in Therapy - Google Patents

Therapy and Use of Compounds in Therapy Download PDF

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Publication number
US20070197485A1
US20070197485A1 US11/627,183 US62718307A US2007197485A1 US 20070197485 A1 US20070197485 A1 US 20070197485A1 US 62718307 A US62718307 A US 62718307A US 2007197485 A1 US2007197485 A1 US 2007197485A1
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US
United States
Prior art keywords
patients
ursodeoxycholic acid
cachexia
endotoxin
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/627,183
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English (en)
Inventor
Stefan Anker
Andrew Coats
Hans-Dieter Volk
Ralf Schuman
Mathias Plauth
Herbert Lochs
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Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Original Assignee
Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9905314.2A external-priority patent/GB9905314D0/en
Priority claimed from GBGB9905307.6A external-priority patent/GB9905307D0/en
Priority claimed from GBGB9905300.1A external-priority patent/GB9905300D0/en
Priority claimed from GBGB9905315.9A external-priority patent/GB9905315D0/en
Priority claimed from GBGB9905310.0A external-priority patent/GB9905310D0/en
Application filed by Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft filed Critical Max Delbrueck Centrum fuer Molekulare in der Helmholtz Gemeinschaft
Priority to US11/627,183 priority Critical patent/US20070197485A1/en
Publication of US20070197485A1 publication Critical patent/US20070197485A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention relates to therapy and the use of agents in the therapy of cachexia and wasting syndromes due to diseases other than congestive heart failure.
  • Cachexia occurs in a number of other chronic diseases, like liver cirrhosis, chronic obstructive pulmonary disease, chronic renal failure, diabetes, rheumatoid arthritis.
  • Cachexia and weight loss are linked to inflammatory processes and they are linked to increased mortality and/or morbidity. Cytokine activation is a potential causal mechanism for the development of cachexia also in these other diseases.
  • the patient has cachexia, as characterised by loss of muscle, fat, and or bone tissue.
  • the patient has experienced weight loss >7.5%.
  • the compound is able to substantially reduce the biological activity of endotoxin (lipopolysaccharide) such that the endotoxin mediated production of inflammatory cytokines in the circulating blood is reduced.
  • endotoxin lipopolysaccharide
  • bile acid we include all naturally occurring bile acids whether from man or from another animal. Also is included bile acids which are synthetic or semi-synthetic derivatives of naturally occurring bile acids. Of course, all bile acids including those that are “naturally occurring” may be synthesised chemically.
  • Bile acids are available from Falk Pharma. GmbH and are described, for example, in WP96/17859, DE29717252 and WO98/05339.
  • Bile acids for use in the method of the invention include, but are not limited to, chemodeoxycholic acid (3d,7 ⁇ -dihydroxy-5-cholan-24-oic-acid), arsodeoxycholic acid (3 ⁇ ,7-dihydroxy-5-cholan-24-oic acid), dehydrocholic acid (3,7,12-trioxo-5-cholan-24-oic acid), cholic acid and deoxycholic acid.
  • the bile acid is a bile acid which is able to form micelles.
  • the bile acid is able to form a micelle around an endotoxin (lipopolysacharide molecule).
  • the bile acid is able to bind to endotoxin (lipopolysaccharide) molecules and substantially reduce the available endotoxin in the patient.
  • the bile acid is able to substantially reduce the biological activity of endotoxin (lipopolysaccharide) such that the endotoxin has a substantially reduced effect on the liver or does not reach the liver in a substantially active form.
  • the bile acid is any one of ursodeoxycholic acid, chemodeoxycholic acid, dehydrocholic acid, cholic acid and deoxycholic acid.
  • the bile acid is ursodeoxycholic acid.
  • Ursodeoxycholic acid has for many years been proposed to be useful also in patients with cholestatic disease, and particularly in patients with primary biliary cirrhosis, a chronic cholestatic liver disease (Lindor et al. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology 1996, 110:1515-1518).
  • UDCA is used in other cholestatic disorders like primary sclerosing cholangitis (Beuerset al: Therapie der autoimmunen Hepatitis, primar biliaren Zirrhose und primär sklerosierenden Cholangitis. Konsensus der Deutschen Deutschen für Verdauungsund Stoff monocytekrank pulp. Z. Gastroenterologie 1997; 35:1041-1049) or benign cholestasis of pregnancy (Palma et al. Ursodeoxycholic acid in the treatment of cholestasis of pregnancy: a randomized, double-blind study controlled with placebo. J Hepatol 1997, 27:1022-1028). Regarding its mode of action, most authorities regard increased bile flow and a reduced hepatocellular insult as a result of improved bile flow and altered bile salt patterns as the main modes of UDCA action in chronic cholestatic liver diseases.
  • ursodeoxycholic acid can not be considered a treatment with proven efficacy in patients with liver disease.
  • ursodeoxycholic acid should be specifically given to patients with cachexia due to liver cirrhosis.
  • ursodeoxycholic acid should be specifically given to patients with alcoholic liver cirrhosis. In fact, such patients were specifically excluded from studies.
  • endotoxaemia occurs in a number of patients with liver cirrhosis. It is not known, whether endotoxin (LPS) levels are particularly raised in patients with cachexia due to liver cirrhosis.
  • LPS endotoxin
  • liver cirrhosis occurs in 30 to 60% of patients with liver cirrhosis, and the survival of patients with cachexia in liver cirrhosis is impaired.
  • Pralauth et al ESPEN guidelines for nutrition in liver disease and transplantation. Clin Nutr 1997, 16:43-55.
  • BCM body cell mass
  • Bile acids can protect the liver against endotoxin action in obstructive jaundice when patients undergo surgery (Greve et al. Bile acids inhibit endotoxin-induced release of tumor necrosis factor by monocytes: an in vitro study. Hepatology Oct. 1, 1989; 10(4):454-458). With regards to monocyte generated cytokine production in response to LPS, in this study deoxycholic acid was the most effective, chenodeoxycholic acid was less effective and ursodeoxycholic acid was ineffective in the concentrations used. Bile acids did not inactivate endotoxin as measured in a chromogenic Limulus amebocyte lysate assay. In these studies patients with non-cholestatic or alcoholic aetiology were not considered, and there was no data or discussion of cachexia and weight loss.
  • ursodeoxycholic acid ursodeoxycholic acid
  • cytokine levels are poor in these studies, and the cellular effects of ursodeoxycholic acid (UDCA) are conflicting.
  • ursodeoxycholic acid should be given in patients with weight loss, i.e. cachexia, in patients with liver disease. It has never been proposed that ursodeoxycholic acid (UDCA) could prevent or reverse weight loss, i.e. cachexia, in patients with liver disease. Additionally, it has never been proposed that ursodeoxycholic acid (UDCA) could prevent or reverse weight loss, i.e. cachexia, in patients with chronic obstructive pulmonary disease, chronic renal failure, diabetes, rheumatoid arthritis.
  • weight loss i.e. cachexia
  • UDCA ursodeoxycholic acid
  • FIG. 1 is a graphical representation showing levels of soluble CD14, TNF- ⁇ and endotoxin in a sampling of patients;
  • FIG. 2 is graphical representation showing the concentration of endotoxin in CHF patients before and after treatment
  • FIG. 3 is a graphical representation showing that Lipoprotein-free serum lacks LPS-neutralizing activity
  • FIG. 4 is a graphical representation showing that certain lipoproteins inhibit LPS-induced TNF- ⁇ release
  • FIG. 5 is a graphical representation showing reduction of TNF- ⁇ release upon increased concentration of high-density lipo proteins in a whole blood sample
  • FIG. 6 is a graphical representation showing that low-density lipoproteins show enhanced neutralization capacity in the presence of increased LBP-concentrations
  • FIG. 7 is a graphical representation showing that addition of LBP to a lipoprotein containing serum reduced LPS-mediated TNF- ⁇ production
  • FIG. 8 is a table showing LPS neutralization by UDCA in whole blood of four healthy patients.
  • FIG. 9 is a table showing LPS neutralization by UDCA in whole blood of patient 1;
  • FIG. 10 is a table showing LPS neutralization by UDCA in whole blood of patient 2;
  • FIG. 11 is a table showing LPS neutralization by UDCA in whole blood of patient 3;
  • FIG. 12 is a table showing LPS neutralization by UDCA in whole blood of patient 4.
  • Heparinized whole blood was diluted 1:10 with medium ⁇ LPS (50 ⁇ g/ml), ⁇ BPi (1 ⁇ g/ml), and ⁇ UDCA (1 ⁇ g/ml-1 mg/ml) according to the manufacturer's recommendation (Milenia whole blood assay; DPC Biermann, Bad Nauheim, Germany) and incubated for 4 hours at 37° C. In the supernatant, we assessed concentrations of TNF and IL-6 using the semiautomated Immulite system (DPC-Biermann, Bad Nauheim, Germany).
  • UDCA reduced LPS-stimulated TNF and IL6 production by 42% and 13%, respectively, ethanol 0.1% alone on average only 9% for TNF and IL6 production increased by 18% for ethanol alone).
  • BPi (1 ug/ml) reduced significantly the spontaneous production of TNF and IL6 of whole blood of patients with cachexia due to liver cirrhosis.
  • TNF and IL6 levels were lowered by at least 5 pg/mi or towards non-detectability, and only in 2 cases TNF and IL6 levels remained stable (p ⁇ 0.05 for changes).
  • Heparinized whole blood was diluted 1:10 with medium ⁇ LPS (50 pg/ml), ⁇ BPI (1 ug/ml), and ⁇ UDCA (1 ug/ml-1 mg/ml) according to the manufacturer's recommendation (Milenia whole blood assay; DPC Biermann, Bad Nauheim, Germany) and incubated for 4 hours at 37° C.
  • concentrations of TNF and IL-6 using the semiautomated Immulite system (DPC-Biermann, Bad Nauheim, Germany).
  • endotoxin LPS
  • sCD14 soluble CD14
  • Soluble CD14 was measured by ELISA (R&D Systems). The majority of patients had a BCM of ⁇ 35% of body weight (mean standard deviation: 25 ⁇ 7%, median 33%, range 11.8-41.9%).
  • Plasma sCDI4 levels were significantly increased in patients (mean ⁇ standard deviation: 4045 ⁇ 623 pg/ml, median 3920 pg/ml, range 2960-5460 pg/ml) compared to sCD14 levels of healthy individuals (mean: 2714 pg/ml, upper limit of normal 3711 pg/ml, as published in Anker et al., Am. J Cardiol 1997; 79;1426-1430).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US11/627,183 1999-03-09 2007-01-25 Therapy and Use of Compounds in Therapy Abandoned US20070197485A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/627,183 US20070197485A1 (en) 1999-03-09 2007-01-25 Therapy and Use of Compounds in Therapy

Applications Claiming Priority (13)

Application Number Priority Date Filing Date Title
GBGB9905314.2A GB9905314D0 (en) 1999-03-09 1999-03-09 Therapy and use of compounds in therapy (2)
GBGB9905307.6A GB9905307D0 (en) 1999-03-09 1999-03-09 Therapy and use of compounds in therapy
GBGB9905300.1A GB9905300D0 (en) 1999-03-09 1999-03-09 Therapy and use of agents in therapy
GB9905310.0 1999-03-09
GB9905300.1 1999-03-09
GB9905314.2 1999-03-09
GBGB9905315.9A GB9905315D0 (en) 1999-03-09 1999-03-09 Therapy and use of compounds in therapy
GB9905307.6 1999-03-09
GB9905315.9 1999-03-09
GBGB9905310.0A GB9905310D0 (en) 1999-03-09 1999-03-09 Therapy and use of compounds in therapy (4)
PCT/EP2000/002062 WO2000053165A2 (en) 1999-03-09 2000-03-09 Use of inhibitors of endotoxin for the treatment of chachexia
US1945202A 2002-02-25 2002-02-25
US11/627,183 US20070197485A1 (en) 1999-03-09 2007-01-25 Therapy and Use of Compounds in Therapy

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2000/002062 Continuation WO2000053165A2 (en) 1999-03-09 2000-03-09 Use of inhibitors of endotoxin for the treatment of chachexia
US1945202A Continuation 1999-03-09 2002-02-25

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US11/627,183 Abandoned US20070197485A1 (en) 1999-03-09 2007-01-25 Therapy and Use of Compounds in Therapy
US12/187,169 Abandoned US20090197851A1 (en) 1999-03-09 2008-08-06 Therapy and use of compounds in therapy

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US (2) US20070197485A1 (de)
EP (2) EP1212064A2 (de)
AT (1) ATE365043T1 (de)
AU (2) AU3809900A (de)
CY (1) CY1107436T1 (de)
DE (1) DE60035262T2 (de)
DK (1) DK1158989T3 (de)
ES (1) ES2288847T3 (de)
PT (1) PT1158989E (de)
WO (2) WO2000053165A2 (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115137733A (zh) * 2022-08-24 2022-10-04 吉林大学 熊去氧胆酸在制备mcr-3酶抑制剂中的应用

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1302206A1 (de) * 2001-10-11 2003-04-16 Universitair Medisch Centrum Utrecht Verfahren und Mittel zur Verwendung des adventitial Toll-like-Rezeptors
US20040122067A1 (en) * 2002-12-20 2004-06-24 Lin Zhao Treatment of chronic heart failure
ATE406172T1 (de) * 2003-03-21 2008-09-15 Bridge Biores Ltd Verwendung von löslichem cd14 zur behandlung von erkrankungen
US7883701B2 (en) * 2003-12-19 2011-02-08 Wisconsin Alumni Research Foundation Method for enhancing growth or increasing feed efficiency through reducing binding between endotoxin and its receptor in the gastrointestinal tract
RU2362570C2 (ru) * 2004-06-02 2009-07-27 Куреха Корпорейшн Средство для устранения фактора циркуляторной дисфункции
TWI487535B (zh) 2004-11-30 2015-06-11 Centocor Inc 類鐸受體３（ｔｏｌｌ ｌｉｋｅ ｒｅｃｅｐｔｏｒ３）拮抗劑，方法及用途
EP1741440A1 (de) * 2005-07-08 2007-01-10 Mellitus S.L. Verwendung von BPI-proteine zur Behandlung von stoffwechselbedingten Erkrankungen und Herzkreislaufstörungen
DK1945820T3 (da) 2005-10-27 2013-11-11 Janssen Biotech Inc Toll-lignende receptor-3-modulatorer, fremgangsmåder og anvendelser
KR100785656B1 (ko) * 2007-05-14 2007-12-17 재단법인서울대학교산학협력재단 소염제로 사용되는 소디움글리코콜레이트 또는 그 유도체
EP2208497A1 (de) * 2009-01-15 2010-07-21 Charité-Universitätsmedizin Berlin (Charité) Verwendung von Ursodesoxycholsäure (UDCA) zum Verbessern des allgemeinen Gesundheitszustands eines Tumorpatienten
CN115120681A (zh) * 2022-07-19 2022-09-30 浙江长三角聚农科技开发有限公司 竹笋生物炭在制备治疗糖尿病及其并发症药物中的应用

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US4377595A (en) * 1979-08-13 1983-03-22 Massachusetts Institute Of Technology Process for reducing depression
US4898879A (en) * 1981-06-29 1990-02-06 Baxter International Inc. Nurtitional composition for management of hepatic failure
US5087453A (en) * 1990-11-01 1992-02-11 Otsuka Pharmaceutical Co., Ltd. Method for the treatment of bacterial caused weight loss and/or hypoglycemia
US5639744A (en) * 1994-04-06 1997-06-17 Alfa Wassermann S.P.A. Bile acids derivatives useful in the therapy of the biliary calculosis from cholesterol and of the pathologies caused by cholestasis
US5869265A (en) * 1993-12-29 1999-02-09 Wake Forest University Ileal bile acid transporter compositions and methods
US6251884B1 (en) * 1995-11-21 2001-06-26 Children's Hospital Medical Center Sulfate conjugates of ursodeoxycholic acid, and their beneficial use in inflammatory disorders and other applications

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US5674855A (en) * 1992-08-12 1997-10-07 The Rogosin Institute Methods and compositions useful in prophylaxis and therapy of endotoxin related conditions
US5998386A (en) * 1997-09-19 1999-12-07 Feldman; Arthur M. Pharmaceutical compositions and method of using same for the treatment of failing myocardial tissue

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4377595A (en) * 1979-08-13 1983-03-22 Massachusetts Institute Of Technology Process for reducing depression
US4898879A (en) * 1981-06-29 1990-02-06 Baxter International Inc. Nurtitional composition for management of hepatic failure
US5087453A (en) * 1990-11-01 1992-02-11 Otsuka Pharmaceutical Co., Ltd. Method for the treatment of bacterial caused weight loss and/or hypoglycemia
US5869265A (en) * 1993-12-29 1999-02-09 Wake Forest University Ileal bile acid transporter compositions and methods
US5639744A (en) * 1994-04-06 1997-06-17 Alfa Wassermann S.P.A. Bile acids derivatives useful in the therapy of the biliary calculosis from cholesterol and of the pathologies caused by cholestasis
US6251884B1 (en) * 1995-11-21 2001-06-26 Children's Hospital Medical Center Sulfate conjugates of ursodeoxycholic acid, and their beneficial use in inflammatory disorders and other applications

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115137733A (zh) * 2022-08-24 2022-10-04 吉林大学 熊去氧胆酸在制备mcr-3酶抑制剂中的应用

Also Published As

Publication number Publication date
WO2000053224A2 (en) 2000-09-14
WO2000053224A3 (en) 2002-04-04
PT1158989E (pt) 2007-10-01
AU4105600A (en) 2000-09-28
EP1212064A2 (de) 2002-06-12
WO2000053165A3 (en) 2001-04-12
AU3809900A (en) 2000-09-28
ES2288847T3 (es) 2008-02-01
WO2000053165A2 (en) 2000-09-14
ATE365043T1 (de) 2007-07-15
DK1158989T3 (da) 2007-10-22
US20090197851A1 (en) 2009-08-06
CY1107436T1 (el) 2012-12-19
DE60035262D1 (de) 2007-08-02
DE60035262T2 (de) 2008-02-21
EP1158989A2 (de) 2001-12-05
EP1158989B1 (de) 2007-06-20

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